Abstract Ongoing Zika virus (ZIKV) outbreaks pose a serious health challenge worldwide. However, very little is known about this virus, including how it replicates and kills host cells. An unbiased genome-wide functional screen for the host factors that facilitate viral replication and ensuing cell death would provide a path to explore host-virus interaction more deeply since viruses rely on host factors for every step of their life cycle. Here we propose to systematically identify ZIKV host factors in human cells with a genome-wide knockout screening method based on CRISPR- Cas9 that we have developed independently. In preliminary studies, we have identified host factors with high sensitivity and specificity and more importantly, strong phenotypes for West Nile virus (WNV), which is a close flavivirus family member of ZIKV. In addition, we also seek to improve our screening strategy so that host genes with weaker phenotypes will also be identified. Thus, we expect to identify ZIKV host factors to construct a comprehensive human host factor?virus interaction map, and to identify potential therapeutic targets for ZIKV.